Epithelial-mesenchymal transition (EMT), a key step in the early stages of cancer metastasis, is orchestrated by several signaling pathways, including IL-6/JAK/STAT3 and TGF-β/Smad signaling. However, an association between the two signaling pathways during the EMT process is largely unknown. Here, we focused on lung cancer and demonstrated that TGF-β1 induced the phosphorylation of Smad3 (p-Smad3), upregulation of Snail, a fibroblast-like morphology, and downregulation of E-cadherin as well as upregulation of vimentin in lung cancer cell lines. SIS3 (an inhibitor of Smad3) suppressed TGF-β1-induced activation of Smad3, upregulation of Snail and the EMT process. Importantly, the JAK2/STAT3-specific inhibitor AG490 blocked Stat3 phosphorylation, resulting in attenuated levels of TGF-β1-induced p-Smad3, Snail, MMP2, and Smad-mediated PAI-1 promoter reporter gene activity in A549 and H1650 cells. Subsequently, AG490 inhibited TGF-β-induced cell migration and invasion. Moreover, exogenous IL-6 treatment stimulated Stat3 activation, enhanced TGF-β-induced expression of p-Smad3 and Snail, aggravated the EMT process, and increased lung cancer cell migration and invasion induced by TGF-β1. Our findings show that the JAK/STAT3 pathway is required for TGF-β-induced EMT and cancer cell migration and invasion via upregulation of the expression of p-Smad3 and Snail, and the IL-6/JAK/STAT3 and TGF-β/Smad signaling synergistically enhance EMT in lung carcinomas. The present study suggests a novel rationale for inhibiting cancer metastasis using anti-IL-6/JAK/STAT3 and anti-TGF-β/Smad therapeutic strategies.

TGFβR1 plays an important role in TGF-β signaling transduction and serves as a tumor suppressor. Our previous studies show that reduced expression of TGFβR1 is common in non-small cell lung cancer (NSCLC) and TGFβR1 variants confer risk of NSCLC. However, the epigenetic mechanisms underlying the role of TGFβR1 in NSCLC carcinogenesis are still elusive. We investigated the function and regulation of TGF-β signaling-based miRNAs in NSCLC. Computational algorithms predicted that the 3'-untranslated region (3'-UTR) of TGFβR1 is a target of miR-142-3p. Here a luciferase reporter assay confirmed that miR-142-3p can directly bind to 3'-UTR of TGFβR1. Overexpression of miR-142-3p in NSCLC A549 cells suppressed expression of TGFβR1 mRNA and protein, while knockdown of endogenous miR-142-3p led to increased expression of TGFβR1. On TGF-β1 stimulation, stable overexpression of miR-142-3p attenuated phosphorylation of SMAD3, an indispensable downstream effector in canonical TGF-β/Smad signaling, via repression of TGFβR1 in A549 cells. Furthermore, miR-142-3p-mediated down-regulation of TGFβR1 weakened TGF-β-induced growth inhibition effect, and this effect was reversed by stable knockdown of endogenous miR-142-3p in A549 cells. In NSCLC tissues, miR-142-3p expression was increased and inversely correlated with TGFβR1 expression. These data demonstrate that miR-142-3p influences the proliferation of NSCLC cells through repression of TGFβR1.

Background and objectiveHenoch-Schönlein purpura (HSP) is an important cause of chronic kidney disease in children. This meta-analysis identified risk factors associated with renal involvement in childhood HSP.MethodsPubMed, Embase, and Web of Science were searched. The quality of all eligible studies was assessed using the Newcastle-Ottawa scale criteria. An analysis of possible risk factors was conducted to report the odds ratio (OR) and weighted mean difference (WMD).ResultsThirteen studies (2398 children) revealed 20 possible and 13 significant risk factors associated with renal involvement in HSP, with the following meta-analysis estimates of OR and WMD, with 95% confidence intervals: older age (0.90, 0.61–1.19); age > 10 y (3.13, 1.39–7.07); male gender (1.36, 1.07–1.74); abdominal pain (1.94,1.24–3.04); gastrointestinal bleeding (1.86, 1.30–2.65); severe bowel angina (3.38, 1.17–9.80); persistent purpura (4.02, 1.22–13.25); relapse (4.70, 2.42–9.14); WBC > 15 × 109/L (2.42, 1.39–4.22); platelets > 500 × 109/L (2.98, 1.22–7.25); elevated antistreptolysin O (ASO) (2.17, 1.29–3.64); and decreased complement component 3 (C3) (3.13, 1.62–6.05). Factors not significantly associated with renal involvement were: blood pressure; orchitis; elevated C-reactive protein; elevated erythrocyte sedimentation rate (ESR); and elevated serum IgA/IgE or IgG. Arthritis/arthralgia may be a risk factor according to the criteria of the American College of Rheumatology (1.41, 1.01–1.96).ConclusionThe following are associated with renal involvement in pediatric HSP: male gender; > 10 y old; severe gastrointestinal symptoms (abdominal pain, gastrointestinal bleeding, and severe bowel angina); arthritis/arthralgia; persistent purpura or relapse; WBC > 15 × 109/L; platelets > 500 × 109/L; elevated ASO; and low C3. Relevant clinical interventions for these risk factors may exert positive effects on the prevention of kidney disease during the early stages of HSP. However, the results should be interpreted cautiously due to the limitations of the studies.

Background: This work aims to explore the role of Th17 and IL-17 signaling in the pathogenesis of primary nephrotic syndrome (PNS) in children and podocyte injury, children with PNS were divided into minimal change nephrotic syndrome (MCNS) and non-minimal change nephrotic syndrome [NMCNS, including mesangial proliferative glomerulonephritis (MsPGN) and focal segmental glomerulosclerosis (FSGS)]. Methods: Flow cytometry (FCM) was used to observe the circulating frequency of Th17 cells and the apoptosis of podocytes by annexinV-FITC/PI. Serum IL-1β and IL-6 levels were measured using enzyme-linked immunosorbent assay. The Fas and FasL expressions in podocytes were examined by FCM analysis using a direct immunofluorescence method. Reverse transcription polymerase chain reaction was applied to measure the mRNA expressions of RORc, IL-23p19, Nephrin, WT1, Synaptopodin, Podocalyxin, Fas, and FasL. The IL-17 and IL-1β expression in renal biopsy tissue was detected by immunohistochemistry. The expressions of WT1, Caspase 8, and Caspase 3 in podocyte cell culture were also measured using immunocytochemistry. Results: Circulating frequencies of Th17 cells, mRNA levels of RORc and IL-23p19, and serum levels of IL-6 and IL-1β were higher in the MCNS and NMCNS groups than in the control group (all P < 0.05), and were higher in the NMCNS group than in the MCNS group (all P < 0.05). The expressions of IL-17 and IL-1β in renal biopsy tissue were higher in the MCNS, MsPGN, and FSGS groups than in the control group (all P < 0.05). Recombinant murine IL-17 (rmIL-17) had no effect on the expressions of Nephrin, Synaptopodin, and WT1 of mouse podocytes, but caused an decrease in the expression of podocalyxin as well as promoted apoptosis in a dose- and time-dependent fashion. Moreover, rmIL-17 increased the expression of Fas, Casepase-8, and Casepase-3, but had no effect on that of FasL. Conclusion: Th17/IL-17 may contribute to the pathogenesis of PNS by decreasing the podocalyxin level and inducing podocyte apoptosis.

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-Supplemental oxygen treatment in preterm infants may cause bronchopulmonary dysplasia (BPD), which is characterized by alveolar simplification and vascular disorganization. Despite type II alveolar epithelial cell (AEC II) damage being reported previously, we found no decrease in the AEC II-specific marker, surfactant protein C (SP-C), in the BPD model in our previous study. We thus speculated that AEC II injury is not a unique mechanism of BPD-related pulmonary epithelial repair dysfunction and that abnormal transdifferentiation can exist. Newborn rats were randomly assigned to model (85% oxygen inhalation) and control groups (room air inhalation). Expressions of AEC I (aquaporin 5, T1␣) and AEC II markers (SP-C, SP-B) were detected at three levels: 1) in intact lung tissue, 2) in AEC II isolated from rats in the two groups, and 3) in AEC II isolated from newborn rats, which were further cultured under either hyperoxic or normoxic conditions. In the model group, increased AEC I was observed at both the tissue and cell level, and markedly increased transdifferentiation was observed by immunofluorescent double staining. Transmission electron microscopy revealed morphological changes in alveolar epithelium such as damaged AECs, a fused air-blood barrier structure, and opened tight junctions in the model group. These findings indicate that transdifferentiation of AECs is not suppressed but rather is increased under hyperoxic treatment by compensation; however, such repair during injury cannot offset pulmonary epithelial air exchange and barrier dysfunction caused by structural damage to AECs. transdifferentiation; alveolar epithelial cells; hyperoxia; bronchopulmonary dysplasia SUPPLEMENTAL OXYGEN TREATMENT, which is often necessary for preterm infants with respiratory failure, has become a major risk factor for bronchopulmonary dysplasia (BPD), one of the most common, serious complications in preterm infants (6,34). BPD is characterized by high morbidity in infants with very low birth weight (BW Ͻ 1,500 g) soon after birth and may induce multiple complications in respiratory and nervous systems during adolescence (4, 6). Despite several decades of research, the underlying pathophysiological foundation of BPD has not been completely clarified.Lung tissue consists of many different cell types, and a developmental disorder of alveolar epithelial cells (AEC) is likely a major cause of BPD (40). The alveolar area accounts for Ն99% of the internal surface area of the lungs (49). Mammals have two types of AECs that maintain normal air exchange function by mutual coordination. Type I AEC (AEC I) cover nearly 96% of alveolar spaces and closely adhere to adjacent capillaries. Such cells are the main epithelial constituents of the air-blood barrier (18, 53) and have air exchange functions. Recent studies have revealed that AEC I can also secrete transport proteins to maintain intrapulmonary fluid and electrolyte balance (9,19,22). Type II AEC (AEC II) are located at the corners of alveoli and are more abundant than AEC I bu...

Dysregulated microRNAs play important pathological roles in carcinogenesis that are yet to be fully elucidated. This study was performed to investigate the biological functions of microRNA-320a (miR-320a) in breast cancer and the underlying mechanisms. Function analyses for cell proliferation, cell cycle, and cell invasion/migration, were conducted after miR-320a silencing and overexpression. The specific target genes of miR-320a were predicted by TargetScan algorithm and then determined by dual luciferase reporter assay and rescue experiment. The relationship between miR-320a and its target genes was explored in human breast cancer tissues. We found that miR-320a overexpression could inhibit breast cancer invasion and migration abilities in vitro, while miR-320a silencing could enhance that. In addition, miR-320a could suppress activity of 3′-untranslated region luciferase of metadherin (MTDH), a potent oncogene. The rescue experiment revealed that MTDH was a functional target of miR-320a. Moreover, we found that MTDH was negatively correlated with miR-320a expression, and it was related to clinical outcomes of breast cancer. Further xenograft experiment also showed that miR-320a could inhibit breast cancer metastasis in vivo. Our findings clearly demonstrate that miR-320a suppresses breast cancer metastasis by directly inhibiting MTDH expression. The present study provides a new insight into anti-oncogenic roles of miR-320a and suggests that miR-320a/MTDH pathway is a putative therapeutic target in breast cancer.

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